Special Delivery: can advanced intracellular delivery enable superior cell therapies for solid tumour treatment — and beyond?

Why is there so much excitement about cell therapy for solid tumours?

What obstacles are there for CARs in treating solid tumours?

  • chemokines (chemotaxis-inducing proteins) prevent trafficking of T cells,
  • physical and chemical barriers (concentrated blood vessels, low pH) reduce infiltration,
  • cytokines (proteins that influence cell behaviour) reduce persistence of T cells in the tumour, and
  • sub-clonal populations of cancer cells may exist in a single tumour, reducing efficacy.
  • Viral vectors provide highly efficient gene transfer but are less efficient for some cell types and can only deliver nucleic acids.
  • Electroporation can cause cell damage and could be lethal in multiple doses or for delicate cell types; it may also denature non-nucleic acid cargoes.

Gene editing for souped-up CAR-T cells

Is the delivery vehicle right for the cargo?

  • eliminate the effect of off-target mutations in CRISPR-Cas9;
  • achieve precise antigen presentation on B cells, priming antigen-specific T cells; and
  • potentially boost delivery efficiency when co-delivered with nucleic acids [4].
  • An approach which involves direct penetration of the cell membrane to deliver target material, namely, delivery of CRISPR ribonucleoproteins adsorbed onto nanoneedles [5].
  • Mechanical methods such as squeezing cells through narrow constrictions within microfluidic devices (SQZ Biotech) [6], or subjecting cells to shear stresses that increase the tension on the cell membrane to achieve pore formation and delivery [7].
  • Exosomes which can be used to deliver proteins efficiently through direct fusion with the cell membrane, circumventing some of the issues of endosomal degradation seen with synthetic carrier systems [8].

New CARs for different destinations

Along for the ride: what advantages might advanced intracellular delivery approaches bring?

  • more subtle membrane permeabilisation means, reducing cell damage;
  • increased uniformity of treatment of the cell population, increasing yield and reproducibility;
  • less variability in transfection outcome, reducing downstream processing; and
  • improved scalability and versatility, suited to diverse manufacturing settings.

What is the final destination for non-viral delivery approaches?

Megan McCandless, Imperial

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